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"This paper continues the Mandelkow's fine work trying to unravel the mechanism of PHF formation by in vitro studies of structural changes that occur in tau on aggregation. Their identification of regions of tau that seem to be important for aggregation through beta-sheet formation is probably relevant to the mechanism of PHF formation in AD. They are the only group (to my knowledge) to be able to show formation of true paired helical filament structures using mutant tau constructs. Although this is a rather esoteric point, there is some debate about whether neuronal death in the tau mutation cases involves PHF formation as a necessary step. In one of the mutations they use in their study, P301L, the human disease does not appear to involve extensive PHF formation. The Mandelkows discuss the possible mechanisms of cell death in tau mutation cases at some length, and it is clear that in most cases, more than one mechanism might participate in killing cells. However, these mechanistic studies point to important hypotheses that can be tested in cellular and perhaps animal models. For example, it will be very interesting to see if transgenic mice with the deletion of lysine at position 280 would show early and extensive PHF formation, as this in vitro work clearly suggests. No doubt attempts to make these mice are already underway."—Peter Davies, Albert Einstein College of Medicine, Bronx, New York